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Development of a new treatment targeting RIP2 in inflammatory bowel diseases

Research Project

Project/Area Number 19K08455
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKindai University

Principal Investigator

WATANABE TOMOHIRO  近畿大学, 医学部, 准教授 (40444468)

Co-Investigator(Kenkyū-buntansha) 工藤 正俊  近畿大学, 医学部, 教授 (10298953)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsRIP2 / 炎症性腸疾患 / 炎症性サイトカイン / NOD2 / ATG16L1 / 自然免疫
Outline of Research at the Start

炎症性腸疾患は腸内細菌に対する過剰な自然免疫反応を背景に発症することが明らかになっている。RIP2は腸内細菌に対する自然免疫反応を制御あるいは増強する自然免疫担当分子であるが、RIP2の活性化が炎症性腸疾患の病態に及ぼす効果は明らかになっていない。本研究では炎症性腸疾患の病態解明を「RIP2が誘導する自然免疫反応」という新たな視点から、実験腸炎モデルと炎症性腸疾患の臨床検体の双方を用いて解明することを目指す。さらに、RIP2の活性化制御を用いた炎症性腸疾患の新規治療法を提案する。

Outline of Final Research Achievements

Receptor-interacting protein 2 (RIP2) is a downstream signaling molecule for toll-like receptors (TLRs) and nucleotide-binding oligomerization domain 2 (NOD2). In this study, we addressed whether activation of RIP2 play pathogenic roles in the development of IBD. We found that sensing of commensal intestinal bacteria by TLRs expressed in dendritic cells induces pro-inflammatory cytokine responses through activation of RIP2 and that excessive activation of RIP2 caused the development of experimental colitis. In studies utilizing colonic biopsy samples from IBD patients, activation of RIP2 was parallel to expression of pro-inflammatory cytokines and disease activity. These murine and human IBD studies strongly support that RIP2 can be a novel treatment target for IBD.

Academic Significance and Societal Importance of the Research Achievements

サイトカインを標的とする生物製剤の登場により、炎症性腸疾患患者の寛解導入率は向上した。しかしながら、現行の生物製剤を用いても、炎症性腸疾患の寛解導入成功率は約50%に留まっている。このように、炎症性腸疾患の新規治療法開発はUnmet medical needsの一つである。本研究では、RIP2というこれまで注目されていなかった分子に着目し、RIP2の活性化という視点から炎症性腸疾患の病態解明を試みた。その結果、RIP2の活性化が炎症性腸疾患の発症に重要な役割を果たすことを明らかにした。この成果はRIP2を標的とする炎症性腸疾患の新規治療薬開発につながるものである。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (16 results)

All 2022 2021 2020 2019

All Journal Article (11 results) (of which Peer Reviewed: 10 results,  Open Access: 5 results) Presentation (5 results) (of which Invited: 2 results)

  • [Journal Article] Expression levels of cellular inhibitor of apoptosis proteins and colitogenic cytokines are inversely correlated with the activation of interferon regulatory factor 42022

    • Author(s)
      Masaki Sho、Watanabe Tomohiro、Arai Yasuyuki、Sekai Ikue、Hara Akane、Kurimoto Masayuki、Otsuka Yasuo、Masuta Yasuhiro、Yoshikawa Tomoe、Takada Ryutaro、Kamata Ken、Minaga Kosuke、Yamashita Kouhei、Kudo Masatoshi
    • Journal Title

      Clinical and Experimental Immunology

      Volume: - Issue: 3 Pages: 340-350

    • DOI

      10.1093/cei/uxac005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IL-33 as a Critical Cytokine for Inflammation and Fibrosis in Inflammatory Bowel Diseases and Pancreatitis2021

    • Author(s)
      Kurimoto Masayuki、Watanabe Tomohiro、Kamata Ken、Minaga Kosuke、Kudo Masatoshi
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 781012-781012

    • DOI

      10.3389/fphys.2021.781012

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease2021

    • Author(s)
      Minaga Kosuke、Watanabe Tomohiro、Hara Akane、Yoshikawa Tomoe、Kamata Ken、Kudo Masatoshi
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 713779-713779

    • DOI

      10.3389/fimmu.2021.713779

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] NOD2 deficiency protects mice from the development of adoptive transfer colitis through the induction of regulatory T cells expressing forkhead box P32021

    • Author(s)
      Takada Ryutaro、Watanabe Tomohiro、Hara Akane、Sekai Ikue、Kurimoto Masayuki、Otsuka Yasuo、Masuta Yasuhiro、Yoshikawa Tomoe、Kamata Ken、Minaga Kosuke、Kudo Masatoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 568 Pages: 55-61

    • DOI

      10.1016/j.bbrc.2021.06.068

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RIPK2 as a New Therapeutic Target in Inflammatory Bowel Diseases2021

    • Author(s)
      Honjo Hajime、Watanabe Tomohiro、Kamata Ken、Minaga Kosuke、Kudo Masatoshi
    • Journal Title

      Frontiers in Pharmacology

      Volume: 12 Pages: 650403-650403

    • DOI

      10.3389/fphar.2021.650403

    • Related Report
      2021 Annual Research Report
    • Open Access
  • [Journal Article] ATG16L1 negatively regulates RICK/RIP2-mediated innate immune responses2020

    • Author(s)
      Honjo Hajime、Watanabe Tomohiro、Arai Yasuyuki、Kamata Ken、Minaga Kosuke、Komeda Yoriaki、Yamashita Kouhei、Kudo Masatoshi
    • Journal Title

      International Immunology

      Volume: 33 Issue: 2 Pages: 91-105

    • DOI

      10.1093/intimm/dxaa062

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Gut microbiome alterations in type 1 autoimmune pancreatitis after induction of remission by prednisolone2020

    • Author(s)
      Kamata K.、Watanabe T.、Minaga K.、Hara A.、Sekai I.、Otsuka Y.、Yoshikawa T.、Park A.‐M.、Kudo M.
    • Journal Title

      Clinical & Experimental Immunology

      Volume: 202 Issue: 3 Pages: 308-320

    • DOI

      10.1111/cei.13509

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease2020

    • Author(s)
      Minaga Kosuke、Watanabe Tomohiro、Hara Akane、Kamata Ken、Omoto Shunsuke、Nakai Atsushi、Otsuka Yasuo、Sekai Ikue、Yoshikawa Tomoe、Yamao Kentaro、Takenaka Mamoru、Chiba Yasutaka、Kudo Masatoshi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 14879-14879

    • DOI

      10.1038/s41598-020-71848-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activation of interferon regulatory factor 7 in plasmacytoid dendritic cells promotes experimental autoimmune pancreatitis2020

    • Author(s)
      Minaga K, Watanabe T, Arai Y, Shiokawa M, Hara A, Yoshikawa T, Kamata K, Yamashita K, Kudo M
    • Journal Title

      J Gastroenterol

      Volume: - Issue: 5 Pages: 565-576

    • DOI

      10.1007/s00535-020-01662-2

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells2019

    • Author(s)
      Kamata Ken、Watanabe Tomohiro、Minaga Kosuke、Hara Akane、Yoshikawa Tomoe、Okamoto Ayana、Yamao Kentaro、Takenaka Mamoru、Park Ah-Mee、Kudo Masatoshi
    • Journal Title

      International Immunology

      Volume: 31 Issue: 12 Pages: 795-809

    • DOI

      10.1093/intimm/dxz050

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] RICK/RIP2 is a NOD2-independent nodal point of gut inflammation2019

    • Author(s)
      Watanabe Tomohiro、Minaga Kosuke、Kamata Ken、Sakurai Toshiharu、Komeda Yoriaki、Nagai Tomoyuki、Kitani Atsushi、Tajima Masaki、Fuss Ivan J、Kudo Masatoshi、Strober Warren
    • Journal Title

      International Immunology

      Volume: 31 Issue: 10 Pages: 669-683

    • DOI

      10.1093/intimm/dxz045

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] クローン病疾患感受性遺伝子 NOD2 の欠損は T 細胞依存性腸炎の発症を抑制する2022

    • Author(s)
      高田隆太郎, 渡邉 智裕, 工藤 正俊
    • Organizer
      第108回日本消化器病学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腸内細菌から紐解く膵臓・腸管臓器関連;自己免疫性炎からの考察2022

    • Author(s)
      渡邉智裕
    • Organizer
      第 2章 腸内微生物叢研究の最前線シリーズ
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 腸内細菌と臓器連関2021

    • Author(s)
      渡邉智裕
    • Organizer
      日本消化器病学会近畿支部 第66回教育講演会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ATG16L1はRICK/RIP2シグナル伝達経路を抑制する2020

    • Author(s)
      本庶元, 渡邉智裕, 工藤正俊
    • Organizer
      JDDW2020
    • Related Report
      2020 Research-status Report
  • [Presentation] RICK/RIP2 is a NOD2-independent nodal point of gut inflammation2019

    • Author(s)
      Watanabe Tomohiro
    • Organizer
      International Congress of Mucosal Immunology
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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